Long-Term Angiotensin II Blockade May Improve Not Only Hyperglycemia but Also Age-Associated Cardiac Fibrosis
Long-Term Angiotensin II Blockade May Improve Not Only Hyperglycemia but Also Age-Associated Cardiac Fibrosis
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DOI：
10.1254/jphs.08210fp
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发表时间：
2009-02-01
影响因子：
3.5
通讯作者：
Miyazaki, Mizuo
中科院分区：
文献类型：
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作者：
Jin, Denan;Takai, Shinji;Miyazaki, Mizuo
在本研究中，长期的血管紧张素（Ang）II拮抗剂对发展的心脏和内皮功能障碍的影响进行了检查在自发性糖尿病托里（SDT）大鼠。未处理的SDT大鼠的血糖浓度从20周龄开始显著增加，而坎地沙坦西来替处理的SDT大鼠的血糖浓度显著降低，直到30周龄。SDT大鼠心功能明显下降，并伴有严重的心肌纤维化、心肌肥大和心肌细胞显微结构的病理改变。在年龄匹配的Sprague道利（SD）大鼠中，心脏功能保存得非常好，但心脏纤维化随着年龄的增长而发展。坎地沙坦酯治疗改善SDT大鼠的心脏结构重塑和心功能。令人惊讶的是，坎地沙坦西来替治疗的SDT大鼠的心脏纤维化程度低于SD大鼠。免疫组织化学染色证实，除了胶原沉积，成纤维细胞和肌成纤维细胞是心脏纤维化区域的主要细胞成分。糖尿病心脏ACE、Ang Ⅱ和AT Ⅱ受体染色阳性。SDT大鼠还表现出内皮功能下降，坎地沙坦酯治疗后有所改善。这些发现表明，Ang U通过在高血糖存在下加速心脏重构和心肌细胞损伤而参与心功能不全的发展。另一方面，虽然在正常条件下发生的心脏纤维化的机制可能与高血糖心脏纤维化的机制有很大不同，但Ang II似乎在两者中起着重要作用。
In the present study, the effects of long-term angiotensin (Ang) II antagonism on the development of cardiac and endothelial disorders were examined in Spontaneously Diabetic Torii (SDT) rats. Blood glucose concentration started to increase markedly in the untreated SDT rats from 20 weeks of age, while the blood glucose concentrations of candesartan cilexetil-treated SDT rats were significantly lower until 30 weeks of age. Cardiac function deteriorated in SDT rats and was accompanied by severe cardiac fibrosis, cardiac hypertrophy, and microstructural pathologic change in cardiomyocytes. Cardiac function was very well preserved in the age-matched Sprague Dawley (SD) rats, but cardiac fibrosis developed with aging. Candesartan cilexetil treatment improved cardiac structural remodeling and cardiac function in SDT rats. Surprisingly, the degree of cardiac fibrosis in candesartan cilexetil-treated SDT rats was less than that of SD rats. Immunohistological staining confirmed that in addition to collagen deposition, fibroblasts and myofibroblasts were the main cellular components in the cardiac fibrotic areas. The diabetic hearts showed positive staining for ACE, Ang II, and AT, receptors. SDT rats also showed decreased endothelial function, which was improved with candesartan cilexetil treatment. These findings indicate that Ang U is involved in the development of cardiac dysfunction by accelerating cardiac remodeling and cardiomyocyte damage in the presence of hyperglycemia. On the other hand, although the mechanisms responsible for the cardiac fibrosis that occurs under normal conditions may differ greatly from those responsible for cardiac fibrosis with hyperglycemia, Ang II seems to play an important role in both.